C1qTNF-related protein 1 attenuates doxorubicin-induced cardiac injury via activation of AKT
C1qTNF-related protein 1 attenuates doxorubicin-induced cardiac injury via activation of AKT
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C1qTNF 相关蛋白 1 通过激活 AKT 减轻阿霉素诱导的心脏损伤
DOI：
10.1016/j.lfs.2018.06.029
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发表时间：
2018-08-15
期刊：
影响因子：
6.1
通讯作者：
Liu, Yuzhou
中科院分区：
文献类型：
--
作者：
Chen, Hongrui;Gao, Lu;Liu, Yuzhou
目的：阿霉素(Dox)具有不可逆的退行性心脏毒性，其临床应用受到限制，但导致这种病理反应的确切机制尚不清楚。C1q/肿瘤坏死因子相关蛋白1(CTRP1)是C1q家族中的一种保守蛋白，具有显著的代谢和心血管功能。然而，CTRP1是否能减轻Dox诱导的心脏损伤仍不清楚。本研究旨在探讨CTRP1对Dox心脏毒性的影响，并探讨其作用机制。材料和方法：利用体内基因递送系统调控CTRP1在心脏中的表达。基因传递两周后，小鼠一次腹腔注射Dox(20 mg/kg)以诱导心脏损伤。关键发现：DOX处理的小鼠心脏CTRP1蛋白水平降低。在Dox处理的小鼠中，CTRP1过表达降低了血浆心肌肌钙蛋白I，恢复了心功能，减少了心肌细胞的凋亡。CTRP1还可提高细胞活力，减少乳酸脱氢酶的体外释放。DOX导致蛋白激酶B(PKB/AKT)磷酸化水平降低，CTRP1过表达可使其恢复。AKT抑制作用抵消了CTRP1对体外培养心肌细胞凋亡的抑制作用。CTRP1对Dox诱导的AKT缺陷小鼠心脏损伤失去保护作用。结论：CTRP1通过激活AKT对Dox诱导的心脏毒性具有保护作用。CTRP1具有治疗多柔比星心脏毒性的潜力。
Aims: The clinical use of doxorubicin (Dox) is limited due to a degenerative irreversible cardiac toxicity, but the precise mechanisms that contribute to this pathological response are not understood. C1q/TNF-related protein 1 (CTRP1), which is a conserved protein of the C1q family, has notable metabolic and cardiovascular functions. However, whether CTRP1 can attenuate Dox-induced cardiac injury remains unclear. Our study aimed to investigate the effect of CTRP1 on Dox-induced cardiotoxicity and assessed the mechanisms of this effect.Materials and methods: We manipulated CTRP1 expression in the heart using in vivo gene delivery system. Two weeks after gene delivery, the mice received a single intraperitoneal injection of Dox (20 mg/kg) to induce cardiac injury.Key findings: Cardiac CTRP1 protein levels were decreased in DOX-treated mice. CTRP1 overexpression reduced plasma cardiac troponin I, restored cardiac function and attenuated cardiomyocyte apoptosis in Dox-treated mice. CTRP1 also improved cell viability and reduced lactate dehydrogenase release in vitro. Dox resulted in the decreased the protein kinase B (PKB/AKT) phosphorylation, which were restored by CTRP1 overexpression. AKT inhibition offset the inhibitory effects of CTRP1 on myocyte apoptosis in vitro. CTRP1 lost its protection against Dox-induced cardiac injury in mice with AKT deficiency. Furthermore, infusion of recombinant CTRP1 protein could reverse pre-established injury in heart induced by Dox treatment.Significance: In conclusion, CTRP1 protected against Dox-induced cardiotoxicity via activation of AKT. CTRP1 has the therapeutic potential to treat Dox-induced cardiotoxicity.